The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery

Abstract

Parallel library synthesis is an important tool for drug discovery because it enables the synthesis of closely related analogues in parallel via robust and general synthetic transformations. In this perspective, we analyzed the synthetic methodologies used in >5000 parallel libraries representing 15 prevalent synthetic transformations. The library data set contains complex substrates and diverse arrays of building blocks used over the last 14 years at AbbVie. The library synthetic methodologies that have demonstrated robustness and generality with proven success are described along with their substrate scopes. The evolution of the synthetic methodologies for library synthesis over the past decade is discussed. We also highlight that the combination of parallel library synthesis with high-throughput experimentation will continue to facilitate the discovery of library-amenable synthetic methodologies in drug discovery.

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

“…Peptides, proteins, clinically approved synthetic and naturally occurring drug molecules, as well as a wide variety of chemical probes contain at least one amide functionality [1–3] . The synthesis of amide bonds remains one of the most frequently performed reactions; accordingly, amide formation reactions represent around 16 % of the total reactions employed for the synthesis of new drugs [4,5] …”

“…[1][2][3] The synthesis of amide bonds remains one of the most frequently performed reactions; accordingly, amide formation reactions represent around 16 % of the total reactions employed for the synthesis of new drugs. [4,5] The amide group deserves a special role among functional groups contained in marketed drugs and clinical candidates, due to its unique hydrogen bonding capability. If one considers the prevailing keto tautomer, an amide group contains two types of hydrogen bonding sites, namely the carbonyl group acting as a hydrogen bond acceptor, and the amine group behaving as hydrogen bond donor.…”

Miniaturization of Popular Reactions from the Medicinal Chemists’ Toolbox for Ultrahigh-Throughput Experimentation

“…1-3 A suite of trustworthy reactions -namely amide coupling, Suzuki coupling, heteroatom arylation such as Buchwald-Hartwig coupling, heteroatom alkylation by reductive amination, and N-Boc deprotection -have emerged as reactions of choice for pharmaceutical chemical space exploration (Figure 1). 1,[4][5][6] These reactions are the workhorses of medicinal chemistry and allow many chemical analogs to be simultaneously prepared, either manually or automated in arrays of glass vials, 7,8 in wellplates, 6,9,10 or in flow. [11][12][13] Inspired by Moore's Law of transistor miniaturization, 14 label-free reaction miniaturization has emerged as a technology with considerable promise to enable systems-level studies of the seemingly infinite chemical and reaction condition space.…”

“…Reductive amination is another of the most popular transformations used in medicinal chemistry. 5,6 A common set of room temperature reaction conditions employs NaBH(OAc)3 31 and acetic acid in 1,2dichloroethane (DCE) or MeCN, 32 while DMAc, another popular solvent, 33 could be used for miniaturized synthesis. While reductive amination has been a popular choice for library synthesis in drug discovery on the milligram scale, 6,34 we set our ambitions on the microgram-scale diversification of the precious natural product staurosporine 36.…”

“…5,6 A common set of room temperature reaction conditions employs NaBH(OAc)3 31 and acetic acid in 1,2dichloroethane (DCE) or MeCN, 32 while DMAc, another popular solvent, 33 could be used for miniaturized synthesis. While reductive amination has been a popular choice for library synthesis in drug discovery on the milligram scale, 6,34 we set our ambitions on the microgram-scale diversification of the precious natural product staurosporine 36. A preliminary study on the reductive amination of 36 with aldehydes and ketones revealed that Ti(O i Pr)4, a common additive, [35][36][37] was key to achieving high conversion.…”